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化学进展 2022, Vol. 34 Issue (4): 773-786 DOI: 10.7536/PC210901   后一篇

• 综述 •

外泌体递药系统及其在肿瘤治疗中的应用

陈晓峰, 王开元, 梁芳铭, 姜睿祺, 孙进*()   

  1. 沈阳药科大学 无涯创新学院 沈阳 110016
  • 收稿日期:2021-09-01 修回日期:2021-12-04 出版日期:2022-04-24 发布日期:2022-05-10
  • 通讯作者: 孙进
  • 作者简介:

    孙进 沈阳药科大学无涯创新学院院长,教授,博导。孙进教授长期从事前体药物、纳米药物和仿生药物递送系统的研究。享受国务院政府特殊津贴,曾获评教育部“长江学者特聘教授”、中组部“万人计划”科技创新领军人才、科技部“中青年科技领军人才”、教育部“新世纪优秀人才支持计划”、辽宁省特聘教授、中国药学会-石药集团青年药剂学奖;担任辽宁省“兴辽英才科技创新团队”负责人、辽宁省“药用辅料与包材工程技术研究中心”主任、沈阳市“生物药剂学”重点实验室负责人、Asian Journal of Pharmaceutical Sciences副主编。

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Exosomes Drug Delivery Systems and Their Application in Tumor Treatment

Xiaofeng Chen, Kaiyuan Wang, Fangming Liang, Ruiqi Jiang, Jin Sun()   

  1. Wuya College of Innovation, Shenyang Pharmaceutical University,Shenyang 110016, China
  • Received:2021-09-01 Revised:2021-12-04 Online:2022-04-24 Published:2022-05-10
  • Contact: Jin Sun

癌症是世界上第二大死亡原因,其每年的发病率都很高。尽管现有的治疗方法在过去十年中取得了重大进展。但是由于现有多数抗肿瘤药物具有非特异性细胞毒性、生物相容性差和生物利用度低等缺点,导致化疗等方法的治疗效果较差。外泌体是由多种细胞分泌的囊泡,具有磷脂双层结构和纳米颗粒大小。它具有良好的生物相容性、高稳定性和良好的靶向性。在癌症治疗中,外泌体作为一种潜在有效的药物递送系统已经引起越来越多的关注。本文综述了外泌体作为靶向肿瘤药物载体的设计策略,并试图为基于外泌体的纳米载体在各种肿瘤治疗中的应用提供新的见解。

关键词： 外泌体, 药物载体, 肿瘤治疗, 递送系统

Cancer is the second leading cause of death in the world, and the incidence rate of cancer remains high every year. Although existing treatments have made significant progress in the past decade, due to the non-specific cytotoxicity, poor biocompatibility and low bioavailability of existing anti-tumor drugs, the therapeutic effect of chemotherapy and other methods is poor. Exosomes are membrane vesicles secreted by various kinds of cells with phospholipid bilayer structure and nano particle size (30~100 nm). Exosomes are the media of information exchange and material transportation between cells, carrying proteins, lipids, nucleic acids and other substances of host cells. With the in-depth study of exosomes, their application is more and more widespread. In the process of intercellular communication, exosomes can regulate the biological response of target cells, which may promote or inhibit disease. They have good biocompatibility, high stability and excellent targetability. Exosomes serving as potentially effective drug delivery systems in cancer treatment have attracted increasing attention. In order to enhance the therapeutic effect of exosomes and reduce the toxicity of drugs to normal cells, it is necessary to improve the targetability of exosomes. Researchers try to customize exosomes with different targeting categories and abilities by modifying exosomes in various ways, which endows exosomes with broad prospects in the field of targeted therapy of tumors. This review highlights the design strategy of exosomes as drug carriers to target tumors, and tries to provide new insights of exosomes-based nanocarriers in various tumor treatment. Besides, this review mainly introduces the biogenesis of exosomes, the physiological function of exosomes and their separation methods. Particular attention is paid to the design strategy of engineered exosomes targeting tumors, including using exosomes from different sources, different surface modification methods and different stimuli-responsive exosomes. Finally, we summarize and discuss the progress of exosomes as drug carriers to solid tumors, and the deficiencies of exosomes in clinical application.

Contents

1 Introduction

2 Exosomes and their characteristics

2.1 Composition of exosomes

2.2 Biogenesis of exosomes

2.3 Physiological function of exosomes

2.4 Isolation of exosomes

2.5 Drug loading mechanism of exosomes

3 The design strategy of engineered exosomes targeting tumors

3.1 Exosomes from different cell sources

3.2 Surface modification of exosomes

3.3 Stimuli-responsive exosomes

4 Application of exosomes as drug delivery carriers in tumor therapy

4.1 Lung cancer

4.2 Pancreatic cancer

4.3 Breast cancer

4.4 Colorectal cancer

4.5 Glioblastoma

5 Conclusion and outlook

Key words: exosome, drug carrier, tumor therapy, delivery system
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图1 外泌体的发生[44]
Fig. 1 Biogenesis of exosomes[44]
表1 外泌体分离方法的优缺点对比
Table 1 Comparison of advantages and disadvantages of Isolation of exosomes
Advantages Disadvantages
Ultracentrifugation Operation is simple; Low-cost. Long time required; Low recovery and purity; Demand large sample.
Immunoseparation High recovery and purity; Strong specificity; High sensitivity; Demand small sample. Long time required; High-cost.
Polymer Precipitation Operation is simple; Time saving; Suitable for processing large samples. Low recovery and purity; Low specificity; Polymer produced is difficult to remove.
Size-exclusion Chromatography Operation is simple; Time saving; High recovery and purity. High-cost.
图2 外泌体的分离[40]
Fig. 2 Isolation of exosomes[40]
表2 外泌体载药方法的优缺点对比
Table 2 Comparison of advantages and disadvantages of different techniques for loading cargos in exosomes
Advantages Disadvantages
Electroporation Operation is simple; Suitable for large molecules loading. Low loading efficiency; Destroy the integrity of EVs.
Incubation Operation is simple; No need to add extra active substances. Low loading efficiency.
Sonication High loading efficiency; Sustained drug release; Suitable for small RNAs. Potential deformation of membrane of EVs; Not efficient for hydrophobic drugs.
Click Chemistry No by-products; High Selectivity; Mild reaction conditions; No destruction on the structure and function of exosomes. Copper can be easily oxidized and inactivated.
图3 E-PSiNPs作为靶向癌症化疗药物载体[56]
Fig. 3 Schematic illustration of E-PSiNPs as drug carriers for targeted cancer chemotherapy[56]
图4 外泌体的化学键合修饰[95]
Fig. 4 Chemical bonding modification of exosomes[95]
图5 载药SMNC-EXOs的构建和递送示意图[98]
Fig. 5 Schematic illustration of construction and delivery of drug-loaded SMNC-EXOs[98]
图6 (A) FA-AuNR@RGD-DOX-Exos的构建、其在近红外照射下的抗肿瘤作用和在荷瘤小鼠模型中评价FA-AuNR@RGD-DOX-Exos治疗效果的示意图。(B) FA-AuNR@RGD-DOX-Exos作为靶向递送和化疗/光热协同肿瘤治疗的纳米平台的示意图[102]
Fig. 6 (A) Schematic illustration of the design of FA-AuNR@RGD-DOX-Exos and their antitumor effect under NIR irradiation. The therapeutic efficiency of FA-AuNR@RGD-DOX-Exos was evaluated in a tumor-bearing mouse model. (B) Schematic illustration of FA-AuNR@RGD-DOX-Exos as a robust nanoplatform for targeted delivery and chemo-photothermal synergistic tumor therapy[102]
图7 内源性纳米声增敏剂用于US以增强靶向递送识别同型癌细胞、刺激反应性药物释放和增强SDT[107]
Fig. 7 Illustration of endogenous nanosonosensitizers for focused US-augmented targeting delivery to recognize homotypic cancer cell, stimuli-responsive drug release, and enhanced SDT[107]
图8 肿瘤衍生外泌体膜修饰的序贯释药、级联增强活化的仿生前药纳米粒的制备及抗乳腺癌转移原理示意图[1]
Fig. 8 Schematic representation of the exosome-like sequential-bioactivating paclitaxel prodrug nanoplatform with CTCs clearance, CuB-mediated metastasis suppression, ROS enhancement, and cascade amplified PTX chemotherapy[1]
图9 RGE-Exo-SPION/Cur的合成示意图[124]
Fig. 9 Schematic representation of RGE-Exo-SPION/Cur synthesis[124]
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